Novel uses of complement inhibitors in myasthenia gravis-Two case reports.

INTRODUCTION/AIMS: Myasthenia gravis (MG) is a rare, life-threatening immune-related adverse effect (irAE) of immune checkpoint inhibitor (ICI) treatment. C5-complement inhibitors are effective treatments for acetylcholine receptor antibody (AChR ab) positive generalized MG. We describe the use of eculizumab/ravulizumab in two patients with MG receiving concomitant pembrolizumab. METHODS: This was a retrospective review of two medical records. RESULTS: Patient 1: An 80-year-old male with recurrent, non-muscle invasive transitional cell carcinoma of the bladder developed ICI-induced AChR ab positive MG (ICI-MG), myositis, and myocarditis 2 weeks after the first dose of pembrolizumab. Myositis responded to corticosteroids. MG responded to eculizumab, followed by ravulizumab. He died of metastatic cancer 8 months later. Patient 2: A 58-year-old male had refractory thymoma-associated AChR ab-positive MG, which responded to eculizumab. He developed metastatic Merkel cell cancer necessitating pembrolizumab. MG remained stable on eculizumab. He had no irAEs for 22 months, with positron emission tomographic resolution of cancer. He then developed mild, indolent retinal vasculitis, which responded to prednisone. Discontinuation of pembrolizumab for 5 months resulted in cancer recurrence; pembrolizumab was resumed with peri-infusion pulse prednisone. MG remained stable and he continues eculizumab. DISCUSSION: In the first patient, eculizumab, followed by ravulizumab, improved ICI-MG. In the second patient, eculizumab treatment may have had a prophylactic effect on the development of ICI-induced irAEs. The effect of complement inhibition on cancer outcomes of ICI therapy is unknown. A possible biologic basis for complement inhibitors in reducing irAEs of ICI, especially in the presence of underlying autoimmune disease, merits evaluation.

Evidence-based management of optic neuritis.

PURPOSE OF REVIEW: Optic neuritis can result from several distinct causes, including multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein antibody disease (MOGAD), when not idiopathic. This review discusses evidence-based treatment approaches contingent upon each specific cause of optic neuritis. RECENT FINDINGS: Current evidence highlights the need for prompt plasmapheresis as adjunct to intravenous methylprednisolone (IVMP) in patients with NMOSD-associated optic neuritis. Recent advances have included a proliferation of novel disease modifying therapies (DMTs) for long-term management of NMOSD and an understanding of how existing therapeutic options can be leveraged to optimally treat MOGAD. SUMMARY: In acute idiopathic or MS-associated optic neuritis, IVMP hastens visual recovery, though it does not substantially affect final visual outcomes. IVMP and adjunctive plasmapheresis are beneficial in the treatment of NMOSD-associated optic neuritis, with a shorter time-to-treatment associated with a higher likelihood of recovery. The natural history of untreated MOGAD-associated optic neuritis is unclear but treatment with IVMP is near-universal given phenotypic similarities with NMOSD. Long-term immunosuppressive therapy is warranted in patients with NMOSD as well as in patients with MOGAD with poor visual recovery or recurrent attacks.

SARS-CoV-2 Parainfectious Optic Neuropathy: 3 Case Reports and a Review of the Literature.

BACKGROUND: Parainfectious optic neuritis is an inflammatory reaction that occurs shortly after an infection without direct invasion by a pathogen. The clinical profile depends on the infectious organism. Cases of SARS-CoV-2 parainfectious optic neuritis have been reported in the literature, but there are no reviews that have applied strict inclusion criteria to more definitively establish the clinical profile associated with SARS-CoV-2. METHODS: We present 3 new cases of SARS-CoV-2 parainfectious optic neuritis. We also review the literature for definite cases by selecting only those with unambiguous clinical features and MRI findings of optic neuritis, positive SARS-CoV-2 polymerase chain reaction or serology, and the absence of myelin oligodendrocyte-glycoprotein or aquaporin-4 antibodies or other diseases associated with optic neuritis. RESULTS: We report 2 cases of monophasic, unilateral SARS-CoV-2 parainfectious optic neuritis with optic disc edema and nadir visual acuities of finger counting. We report 1 case of mild SARS-CoV-2 parainfectious optic neuritis that featured cotton wool spots, peripapillary wrinkles and hemorrhages, and recurrence after an initial steroid taper. We identified 6 cases of unambiguous SARS-CoV-2 parainfectious optic neuritis from the literature. Combining our case series with the case reports in the literature, the average age was 42.8 years, 3/9 had bilateral disease, 6/8 had optic disc edema, 8/9 had nadir visual acuity of finger counting or worse, and all recovered visual acuity to 20/40 or better after therapy with steroids. CONCLUSIONS: SARS-CoV-2 parainfectious optic neuritis has a clinical profile that is atypical for idiopathic optic neuritis but fairly typical of parainfectious forms of optic neuritis with a severely reduced nadir visual acuity, high likelihood of bilaterality, high incidence of optic disc edema, and prompt and significant response to corticosteroids. Further study with long-term follow-up and epidemiologic investigation will be needed to further characterize this clinical entity.

Giant Cell Arteritis Presenting With Multiple Cranial Neuropathies - Case Report.

Background: Vision loss accounts for most ophthalmic presentations of giant cell arteritis (GCA), but an important minority of patients present with diplopia and other cranial neuropathies. Case study: Here we present the case of an 84-year-old woman with a prior history of multiple cancers who was admitted to our hospital after developing double vision. She was found to have mydriasis, ptosis, and ophthalmoplegia in the right eye (OD) consistent with a combined R CNIII/CNVI neuropathy, as well as highly elevated inflammatory markers. Given her cancer history, the patient was initially worked up for various neoplastic, paraneoplastic, inflammatory, and infectious causes of multiple cranial neuropathies; however, as these results were negative, GCA became a more likely contender as a possible rare cause of multiple cranial neuropathies. The patient underwent temporal artery biopsy which showed pathology consistent with giant cell arteritis, and she was treated with steroids with eventual improvement in ophthalmoplegia and ptosis. Conclusions: This case illustrates the importance of recognizing GCA as a rare possible cause of multiple cranial neuropathies, including the indispensable role of temporal artery biopsy.

Fluorescein Angiography Findings in Susac Syndrome: A Multicenter Retrospective Case Series.

BACKGROUND: Susac syndrome is a vasculopathy, resulting in the classic triad of branch retinal artery occlusion (BRAO), inner ear ischemia, and brain ischemia. In this retrospective chart review, we characterize fluorescein angiography (FA) findings and other ancillary studies in Susac syndrome, including the appearance of persistent disease activity and the occurrence of new subclinical disease on FA. METHODS: This multicenter, retrospective case series was institutional review board-approved and included patients with the complete triad of Susac syndrome evaluated with FA, contrasted MRI of the brain, and audiometry from 2010 to 2020. The medical records were reviewed for these ancillary tests, along with demographics, symptoms, visual acuity, visual field defects, and findings on fundoscopy. Clinical relapse was defined as any objective evidence of disease activity during the follow-up period after initial induction of clinical quiescence. The main outcome measure was the sensitivity of ancillary testing, including FA, MRI, and audiometry, to detect relapse. RESULTS: Twenty of the 31 (64%) patients had the complete triad of brain, retinal, and vestibulocochlear involvement from Susac syndrome and were included. Median age at diagnosis was 43.5 years (range 21-63), and 14 (70%) were women. Hearing loss occurred in 20 (100%), encephalopathy in 13 (65%), vertigo in 15 (75%), and headaches in 19 (95%) throughout the course of follow-up. Median visual acuity at both onset and final visit was 20/20 in both eyes. Seventeen (85%) had BRAO at baseline, and 10 (50%) experienced subsequent BRAO during follow-up. FA revealed nonspecific leakage from previous arteriolar damage in 20 (100%), including in patients who were otherwise in remission. Of the 11 episodes of disease activity in which all testing modalities were performed, visual field testing/fundoscopy was abnormal in 4 (36.4%), MRI brain in 2 (18.2%), audiogram in 8 (72.7%), and FA in 9 (81.8%). CONCLUSIONS: New leakage on FA is the most sensitive marker of active disease. Persistent leakage represents previous damage, whereas new areas of leakage suggest ongoing disease activity that requires consideration of modifying immunosuppressive therapy.

Does Tocilizumab Influence Ophthalmic Outcomes in Giant Cell Arteritis?

BACKGROUND: Despite appropriate use of corticosteroids, an important minority of patients with giant cell arteritis (GCA) develop progressive vision loss during the initial stages of the disease or during corticosteroid tapering. Tocilizumab is the only clearly effective adjunctive treatment to corticosteroids in the management of GCA, but questions regarding its efficacy specifically in the neuro-ophthalmic population and its role in mitigating vision loss have not been broached until recently. EVIDENCE ACQUISITION: The authors queried Pubmed using the search terms "GCA" and "tocilizumab" in order to identify English-language publications either explicitly designed to evaluate the influence of tocilizumab on the ophthalmic manifestations of GCA or those which reported, but were not primarily focused on, ophthalmic outcomes. RESULTS: Recent retrospective analyses of populations similar to those encountered in neuro-ophthalmic practice suggest that tocilizumab is effective in decreasing the frequency of GCA relapse, the proportion of flares involving visual manifestations of GCA, and the likelihood of permanent vision loss. Data regarding the utility of tocilizumab to curtail vision loss at the time of diagnosis are limited to case reports. CONCLUSIONS: Compared with conventional corticosteroid monotherapy, treatment of GCA with both corticosteroids and tocilizumab may decrease the likelihood of permanent vision loss. Further prospective, collaborative investigation between rheumatologists and neuro-ophthalmologists is required to clarify the ophthalmic and socioeconomic impact of tocilizumab on the treatment of GCA.

Clinical Correlation Between Vertical Gaze Palsy and Midbrain Volume in Progressive Supranuclear Palsy.

BACKGROUND: Supranuclear vertical gaze palsies and slowed vertical saccades are characteristic clinic features of progressive supranuclear palsy (PSP). The "hummingbird sign," reflective of midbrain atrophy, is a classic radiographic sign of PSP. Correlation between eye movement abnormalities and radiographic findings in PSP has been reported previously. However, due to the use of clinical criteria not commonly employed in neuro-ophthalmic practice and neuroimaging techniques that are not widely available, it remains unclear whether correlation between midbrain structure and characteristic ocular-motor disturbances can be helpful to neuro-ophthalmologists seeking to adjudicate difficult or unusual diagnostic cases. METHODS: Patients with a diagnosis of probable PSP according to Movement Disorders Society criteria were studied retrospectively. A neuroradiologist calculated brainstem volumes in enrolled participants and normal controls. Spearman correlations were used to correlate the extent of eye movement limitation as assessed by 2 neuro-ophthalmologists with brainstem volumes. RESULTS: Fourteen participants with PSP and 15 healthy controls with similar age and gender distribution were enrolled and evaluated retrospectively. All 14 participants with PSP had undergone MRIs. Midbrain atrophy significantly correlated with the PSP rating scale (P < 0.001). PSP patients had significantly reduced volumes in the midbrain (P -0.0026), tegmentum (0.0001), tectum (0.0001), and medulla (P = 0.0024) compared with normal controls. Notes documenting quantified ocular motor function were available in 7 of 14 participants with PSP. Midbrain atrophy significantly correlated with in the extent of upward gaze limitation (P = 0.03). CONCLUSIONS: The severity of upward gaze limitation correlates with the severity of midbrain atrophy in patients with PSP. Recognition of this correlation may help to adjudicate diagnostic dilemmas and guide further evaluation.

Variation in Evolving Optic Neuritis.

BACKGROUND: The typical natural history of optic neuritis is subjected to important exceptions. Recognition of these exceptions has led to valuable insights regarding specific etiologies of optic neuritis. Exceptions to the natural history of recovering optic neuritis are well-defined (e.g., chronic relapsing inflammatory optic neuropathy), but exceptions to the natural history of evolving optic neuritis are less so. METHODS: Medical records of patients illustrating an atypical course of evolving optic neuritis were reviewed in a retrospective manner. Each patient was treated by at least one of the authors. RESULTS: Four patients were identified who illustrated an atypical natural history of incipient optic neuritis. Diagnoses included idiopathic optic neuritis, seropositive neuromyelitis optica spectrum disease, anti-myelin oligodendrocyte glycoprotein antibody disease, and multiple sclerosis in 1 patient each. Features of interest included an atypical temporal relationship between development of pain and onset of clinical optic neuropathy, an unusually protracted duration of pain, and an unusually long duration of worsening optic neuropathy before stabilization. CONCLUSIONS: This case series illustrates the substantial clinical heterogeneity which may be observed in the evolution of optic neuritis. The temporal relationship between development of pain and onset of clinical optic neuropathy, the duration of pain, and duration of worsening optic neuropathy before stabilization are all subjected to significant variability. Although most patients with optic neuritis present with painful vision loss which progresses over 1 week or less, careful attention to the exceptions described herein may facilitate earlier recognition of diagnostically challenging cases.

Fulminant Idiopathic Intracranial Hypertension.

PURPOSE OF REVIEW: The goal of this review is to describe the presenting features of fulminant idiopathic intracranial hypertension (IIH) and outline the multimodal approach to its treatment. RECENT FINDINGS: Venous sinus stenting may be an appropriate alternative to optic nerve sheath fenestration or cerebrospinal fluid shunting in select patients with fulminant IIH. Prompt surgical intervention maximizes the chance of visual recovery in patients with fulminant IIH. "Fulminant IIH" is defined as intracranial hypertension with no secondary cause, severe vision loss within 4 weeks of symptom onset, and progressive vision loss over days. Rapid recognition of the fulminant phenotype of IIH by emergency department physicians, neurologists, and ophthalmologists is critical. Without appropriate triage and rapid medical and surgical intervention, patients with fulminant IIH are at high risk for profound, permanent vision loss. Prompt surgical intervention with optic nerve sheath fenestration, cerebrospinal fluid shunting, or venous sinus stenting minimizes the chance of poor visual outcome. If a delay is anticipated, serial lumbar punctures or temporary cerebrospinal fluid drainage and medical therapy may forestall irreversible vision loss.

The Pupil.

PURPOSE OF REVIEW: The goal of this article is to review the anatomy and physiology of pupillary function and then employ that information to develop a comprehensive framework for understanding and diagnosing pupillary disorders. RECENT FINDINGS: The contribution of rods and cones to the pupillary light reflex has long been known. A third photosensitive cell type, the intrinsically photosensitive retinal ganglion cell, has recently been discovered. This cell type employs melanopsin to mediate a portion of the pupillary light reflex independent of rods and cones (the postillumination pupillary response) and photic regulation of circadian rhythm. SUMMARY: The autonomic nervous system regulates pupil size in response to stimuli. The parasympathetic nervous system causes miosis in response to light and near visual stimuli. These stimuli activate supranuclear pathways that project to the Edinger-Westphal nuclei. The sympathetic nervous system causes mydriasis in response to a variety of arousing factors, both physiologic (wakefulness) and pathologic (pain). Abnormalities of physiologic function cause disturbances of pupil size, shape, and response to stimuli. The clinical approach to pupillary abnormalities should focus on the clinical and pharmacologic assessment of the pupil's expected response to diverse stimuli.

The Comprehensive Management of Cerebellar Ataxia in Adults.

PURPOSE OF REVIEW: In this review, we present the multidisciplinary approach to the management of the many neurological, medical, social, and emotional issues facing patients with cerebellar ataxia. RECENT FINDINGS: Our holistic approach to treatment, developed over the past 25 years in the Massachusetts General Hospital Ataxia Unit, is centered on the compassionate care of the patient and their family, empowering them through engagement, and including the families as partners in the healing process. We present the management of ataxia in adults, beginning with establishing an accurate diagnosis, followed by treatment of the multiple symptoms seen in cerebellar disorders, with a view to maximizing quality of life and effectively living with the consequences of ataxia. We discuss the importance of a multidisciplinary approach to the management of ataxia, including medical and non-medical management and the evidence base that supports these interventions. We address the pharmacological treatment of ataxia, tremor, and other associated movement disorders; ophthalmological symptoms; bowel, bladder, and sexual symptoms; orthostatic hypotension; psychiatric and cognitive symptoms; neuromodulation, including deep brain stimulation; rehabilitation including physical therapy, occupational therapy and speech and language pathology and, as necessary, involving urology, psychiatry, and pain medicine. We discuss the role of palliative care in late-stage disease. The management of adults with ataxia is complex and a team-based approach is essential.

Diplopia after Cataract Extraction.

Diplopia after cataract extraction is an unexpected outcome for the patient and often a source of confusion for the physician, owing to its relative infrequency. This article reviews the pertinent literature on the subject. Mechanisms include anesthetic myotoxicity, surgical trauma, optical aberrations, cortical disorders in patients with congenital strabismus, and the unmasking of previously unnoticed ocular misalignment. As the population continues to age and cataract extraction is performed in increasing volume, familiarity with this uncommon but important outcome may help to clarify and effectively treat post-cataract-extraction diplopia.

Neuroimaging diagnostic and monitoring approaches in ophthalmology.

PURPOSE OF REVIEW: We review new applications of optical coherence tomography (OCT) technology in neuro-ophthalmology. We also describe new technologies for visualizing the extracranial vessels in the diagnosis of giant cell arteritis (GCA). RECENT FINDINGS: Newer OCT modalities are expanding the evaluation of the optic disc, and are being applied to a number of neurologic conditions such as demyelinating and neurodegenerative disease. Swept-source OCT and enhanced-depth imaging OCT are refining the fine-grained analysis of the optic nerve head in the diagnosis of papilledema and optic nerve drusen. OCT-angiography is opening up new avenues to the study of the vasculature of the optic nerve head and its disorders, including ischemic optic neuropathy. Newer technologies in the diagnosis of GCA include vascular ultrasound, magnetic resonance imaging (MRI) of the extracranial vasculature and PET imaging of the large vessels. SUMMARY: OCT and several of its derivations are advancing diagnosis, and in some cases prognostication, in a variety of inflammatory, ischemic and compressive optic neuropathies. These technologies hold potential in the laboratory as well, yielding insights into the mechanisms of a variety of neurological conditions. In addition, further developments in MRI and ultrasonography techniques are shaping the approach to the diagnosis of GCA.